Multiple Myeloma
Conditions
Keywords
Relapsed or refractory Multiple Myeloma
Brief summary
The primary objectives of the study are to evaluate the safety profile and the anti-tumor activity of 2 dose levels of natalizumab in participants with relapsed or refractory multiple myeloma. Secondary objectives are to assess the pharmacokinetic (PK) profile of natalizumab in this study population and to assess peripheral blood mononuclear cell (PBMC) saturation of very late antigen-4 (VLA-4, an α4-integrin) and evaluate possible correlations with clinical activity.
Detailed description
Despite no protocol-defined study stopping criteria being met, the sponsor decided to terminate enrollment after the phase 1 portion was complete and to not move into the phase 2 portion of the study. This decision was made due to difficulty enrolling participants and was not due to any safety concerns.
Interventions
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Relapsed or refractory multiple myeloma that was treated with or was considered inappropriate for treatment with bortezomib and an IMiD® drug (including an analogue). * Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2. * Corrected calcium \<10.6 mg/dL. Key
Exclusion criteria
* Candidates for stem cell transplantation willing to undergo transplantation. (Subjects who are candidates for stem cell transplantation, but are not willing to undergo transplant will be eligible for the study.) * Autologous stem cell transplantation \<3 months post-transplant. * Prior allogeneic stem cell transplantation. * Nonsecretory myeloma. * Plasma cell leukemia (\>2000/µL circulating plasma cells by standard cell counting differential), hyperleukocytosis (white blood cells \>100,000/µL), clinical evidence of hyperviscosity syndrome, or polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome (POEMS), or primary systemic amyloidosis. * Subjects who cannot undergo a brain magnetic resonance imaging (MRI) study. * Clinically significant (as determined by the Investigator) 12 lead electrocardiogram (ECG) abnormalities, including QTc prolongation (\>450 ms in males, \>470 ms in females). NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) | Day 1 up to Day 28 | DLTs = any ≥grade 3 toxicity related to treatment; treatment delays of ≥7 days due to any toxicity related to treatment, with the exception of hepatic transaminases; or alanine and/or aspartate aminotransferase (ALT and/or AST) \>3\*upper limit of normal (ULN) with either a total bilirubin \>2\*ULN or an international normalized ratio (INR) \>1.5 related to treatment, or with the appearance of worsening fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia. |
| Objective Response Rate (ORR) | Day 1 up to Month 6 | Response rates were classified according to the International Uniform Response Criteria for Multiple Myeloma (Durie et al, 2006). |
| Number of Participants With Adverse Events (AEs) | Day 1 up to Month 6 | An AE was defined as any untoward medical occurrence in a participant administered medicinal (investigational) product and that does not necessarily have a causal relationship with this product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. See the adverse events section of the record for more details. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number Of Participants Who Achieve A Complete Response | Day 1 up to Month 6 | Response rates were classified according to the International Uniform Response Criteria for Multiple Myeloma (Durie et al, 2006). Complete Response (CR): negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas , and ≤ 5% plasma cells in the bone marrow. Stringent CR (sCR): CR as defined above, and normal free light chain (FLC) ratio, and absence of clonal cells in the bone marrow by immunohistochemistry or immunofluorescence, based on a κ/λ ratio of \> 4:1 or \< 1:2 performed on a minimum of 100 plasma cells. |
| Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC) | Cycle 1: Day 1 (1 hour before infusion and 1 and 24 hours after infusion), Days 8, 15, 22. Cycles 2-5: 1 hour before and 1 hour after infusion). Cycle 6: Day 1 (1 hour before infusion and 1 hour after infusion), Days 8, 15, 22. | — |
| Kaplan-Meier Estimates for Duration Of Response For Participants With A Response | Day 1 up to Month 6 | Response rates were classified according to the International Uniform Response Criteria for Multiple Myeloma (Durie et al, 2006). Kaplan-Meier methods were used to estimate the median duration of response and associated 95% confidence intervals. |
| Pharmacokinetic (PK) Profile Of Natalizumab | Cycles 1 and 6: Day 1 (before infusion and 0.25, 2, 6 and 24 hours after infusion), Days 8, 15, 22. Cycles 2-5: Day 1 (before infusion and 0.25 hour after infusion) | PK modeling, either compartmental or noncompartmental-based, was used to describe serum concentrations. Standard PK parameters estimated include: area-under-the-concentration-time curve (AUC), maximum-observed concentration (Cmax), time-to-reach maximum concentration (Tmax), total body clearance (Cl), volume of distribution (Vd), and elimination half-life (t1/2). |
Countries
United States
Participant flow
Pre-assignment details
This record includes data up to and including the last data values collected during long-term follow-up (27 January 2010).
Participants by arm
| Arm | Count |
|---|---|
| Natalizumab 300 mg Intravenous (IV) infusions of natalizumab 300 mg once every 28 days for 6 months. | 3 |
| Natalizumab 450 mg Intravenous (IV) infusions of natalizumab 450 mg once every 28 days for 6 months. | 3 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Disease Progression | 2 | 2 |
| Overall Study | No Disease Response After Cycle 6 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Natalizumab 300 mg | Natalizumab 450 mg | Total |
|---|---|---|---|
| Age, Continuous | 67.0 years | 68.0 years | 67.5 years |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs)
An AE was defined as any untoward medical occurrence in a participant administered medicinal (investigational) product and that does not necessarily have a causal relationship with this product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. See the adverse events section of the record for more details.
Time frame: Day 1 up to Month 6
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Natalizumab 300 mg | Number of Participants With Adverse Events (AEs) | 3 participants |
| Natalizumab 450 mg | Number of Participants With Adverse Events (AEs) | 3 participants |
Primary
Number of Participants With Dose Limiting Toxicities (DLTs)
DLTs = any ≥grade 3 toxicity related to treatment; treatment delays of ≥7 days due to any toxicity related to treatment, with the exception of hepatic transaminases; or alanine and/or aspartate aminotransferase (ALT and/or AST) \>3\*upper limit of normal (ULN) with either a total bilirubin \>2\*ULN or an international normalized ratio (INR) \>1.5 related to treatment, or with the appearance of worsening fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia.
Time frame: Day 1 up to Day 28
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Natalizumab 300 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 participants |
| Natalizumab 450 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 participants |
Primary
Objective Response Rate (ORR)
Response rates were classified according to the International Uniform Response Criteria for Multiple Myeloma (Durie et al, 2006).
Time frame: Day 1 up to Month 6
Population: ORR was not calculated because the study was terminated early.
Secondary
Kaplan-Meier Estimates for Duration Of Response For Participants With A Response
Response rates were classified according to the International Uniform Response Criteria for Multiple Myeloma (Durie et al, 2006). Kaplan-Meier methods were used to estimate the median duration of response and associated 95% confidence intervals.
Time frame: Day 1 up to Month 6
Population: Duration of response was not calculated because the study was terminated early.
Secondary
Natalizumab Binding Saturation Of α4 Integrin Sites On Peripheral Blood Mononuclear Cells (PBMC)
Time frame: Cycle 1: Day 1 (1 hour before infusion and 1 and 24 hours after infusion), Days 8, 15, 22. Cycles 2-5: 1 hour before and 1 hour after infusion). Cycle 6: Day 1 (1 hour before infusion and 1 hour after infusion), Days 8, 15, 22.
Population: Analysis of binding saturation of α4 integrin sites was not performed because the study was terminated early.
Secondary
Number Of Participants Who Achieve A Complete Response
Response rates were classified according to the International Uniform Response Criteria for Multiple Myeloma (Durie et al, 2006). Complete Response (CR): negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas , and ≤ 5% plasma cells in the bone marrow. Stringent CR (sCR): CR as defined above, and normal free light chain (FLC) ratio, and absence of clonal cells in the bone marrow by immunohistochemistry or immunofluorescence, based on a κ/λ ratio of \> 4:1 or \< 1:2 performed on a minimum of 100 plasma cells.
Time frame: Day 1 up to Month 6
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Natalizumab 300 mg | Number Of Participants Who Achieve A Complete Response | 0 participants |
| Natalizumab 450 mg | Number Of Participants Who Achieve A Complete Response | 0 participants |
Secondary
Pharmacokinetic (PK) Profile Of Natalizumab
PK modeling, either compartmental or noncompartmental-based, was used to describe serum concentrations. Standard PK parameters estimated include: area-under-the-concentration-time curve (AUC), maximum-observed concentration (Cmax), time-to-reach maximum concentration (Tmax), total body clearance (Cl), volume of distribution (Vd), and elimination half-life (t1/2).
Time frame: Cycles 1 and 6: Day 1 (before infusion and 0.25, 2, 6 and 24 hours after infusion), Days 8, 15, 22. Cycles 2-5: Day 1 (before infusion and 0.25 hour after infusion)
Population: PK analysis was not performed because the study was terminated early.